Ventilation circuit adaptor and proximal aerosol delivery system

ABSTRACT

An adaptor for delivering an aerosolized active agent to a patient with concomitant positive pressure ventilation includes an aerosol flow channel having an aerosol inlet port and a patient interface port, and defining an aerosol flow path from the aerosol inlet port to and through the patient interface port; and a ventilation gas flow channel in fluid communication with the aerosol flow channel and having a gas inlet port and a gas outlet port, and defining a ventilation gas flow path from the gas inlet port to and through the gas outlet port, wherein the ventilation gas flow path is at least partially offset from the aerosol flow path and at least partially encircles the aerosol flow path. Systems and methods for delivering an aerosolized active agent to a patient with concomitant positive pressure ventilation incorporate the adaptor.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of provisional Application Nos.61/069,850, filed Mar. 17, 2008, titled VENTILATION CIRCUIT ADAPTOR and61/076,442, filed Jun. 27, 2008, titled VENTILATION CIRCUIT ADAPTOR ANDPROXIMAL AEROSOL DELIVERY SYSTEM, which are incorporated herein in theirentirety.

BACKGROUND OF THE INVENTION

1. Field of Invention

This invention relates to pulmonary therapy and ventilatory support ofpulmonary function. In particular, the invention is directed to anaerosol delivery system and a ventilation circuit adaptor for pulmonarydelivery of aerosolized substances and/or for other therapeutic and/ordiagnostic purposes, in combination with noninvasive or invasiverespiratory ventilation support.

2. Description of Related Art

Various patents, patent publications and scientific articles may bereferred to throughout the specification. The contents of each of thesedocuments are incorporated by reference herein, in their entireties.

Patients, both adult and infants, in respiratory failure or those withrespiratory dysfunction are typically mechanically ventilated in orderto provide suitable rescue and prophylactic therapy. Respiratory failurein adults or infants can be caused by any condition relating to poorbreathing, muscle weakness, abnormality of lung tissue, abnormality ofthe chest wall, and the like. Additionally, pre- and full-term infantsborn with a respiratory dysfunction, such as respiratory distresssyndrome (RDS), meconium aspiration syndrome (MAS), persistent pulmonaryhypertension (PPHN), acute respiratory distress syndrome (ARDS),pheumocystis carinii pneumonia (PCP), transient tachypnea of the newborn(TTN) and the like often require prophylactic or rescue respiratorysupport. In addition to respiratory support, infants suffering from, orat risk of RDS are often treated with exogenous surfactant, whichimproves gas exchange and has had a dramatic impact on mortality.Typically, the exogenous material is delivered as a liquid bolus to thecentral airways via a catheter introduced through an endotracheal tube.Infants born at 28 weeks or less are almost universally intubated andmechanically ventilated. There is a significant risk of failure duringthe process of intubation and a finite chance of causing damage to theupper trachea, laryngeal folds and surrounding tissue. Mechanicalventilation over a prolonged time, particularly where elevated oxygentensions are employed, can also lead to acute lung damage. Ifventilation and oxygen is required for prolonged periods of time and/orif the ventilator is not sufficiently managed, the clinical consequencescan include bronchopulmonary dysplasia, chronic lung disease, pulmonaryhemorrhage, intraventricular hemorrhage, and periventricularleukomalacia.

Infants born of larger weight or gestational age who are not overtly atrisk of developing respiratory distress syndrome, or infants who havecompleted treatment for respiratory distress syndrome can be supportedby noninvasive means. Attempts were made to administer liquid surfactantwithout intubation: to the posterior pharynx through the catheter, withspontaneously breathing infant [1], or to the pharynx through thelaryngeal mask with transient positive pressure ventilation (PPV) [2].Another non-invasive approach is nasal continuous positive airwaypressure ventilation (nCPAP or CPAP). CPAP is a means to providevoluntary ventilator support while avoiding the invasive procedure ofintubation. Nasal CPAP is widely accepted among clinicians as a lessinvasive mode of ventilatory support for preterm newborns withmild/moderate RDS. CPAP has been demonstrated to be effective inincreasing functional residual capacity (FRC) by stabilizing andimproving alveolar function [3], and in dilating the larynx [4]. Basedon animal work, CPAP in combination with surfactant therapy has beenalso shown to minimize the risk for bronchopulmonary dysplasia (BPD)development among preterm baboons [5]. Randomized clinical trialsfocused on the use of nCPAP in the prophylaxis of RDS did show thebenefit of nCPAP after instillation of surfactant via endotracheal tube[6, 7]. CPAP provides humidified and slightly over-pressurized gas(approximately 5 cm H₂O above atmospheric pressure) to an infant's nasalpassageway utilizing nasal prongs or a tight fitting nasal mask. CPAPalso has the potential to provide successful treatment for adults withvarious disorders including chronic obstructive pulmonary disease(COPD), sleep apnea, acute lung injury (ALI)/ARDS and the like.

A typical ventilatory circuit for administering positive pressureventilation includes a positive pressure generator connected by tubingto a patient interface, such as a mask, nasal prongs, or an endotrachealtube, and an exhalation path, such as tubing that allows discharge ofthe expired gases, e.g., to the ventilator or to an underwaterreceptacle as for “bubble” CPAP. The inspiratory and expiratory tubesare typically connected to the patient interface via a “Y” connector,which contains a port for attaching each of the inspiratory andexpiratory tubes, as well as a port for the patient interface and,typically, a port for attaching a pressure sensor. In a closed system,such as with use of a tight-fitting mask or endotracheal tube,administration of other pulmonary treatment, e.g., pulmonary surfactant,or diagnosis generally requires temporary disconnection of theventilatory support while the pulmonary treatment is administered or thediagnosis is conducted.

Recent efforts have focused on delivery of surfactant and/or otheractive agents in an aerosolized form, in order to enhance deliveryand/or avoid or minimize the trauma of prolonged invasive mechanicalventilation. However, if the patient is receiving ongoing ventilatorysupport, administration of aerosolized active agents may necessitateinterruption of the ventilatory support while the aerosol isadministered. As a result, attempts have been made to deliveraerosolized active agents simultaneously with noninvasive positivepressure. For instance, Berggren et al. (Acta Pcediatr. 2000,89:460-464) attempted to delivery pulmonary surfactant simultaneouslywith CPAP, but were unsuccessful due to the lack of sufficientquantities of surfactant reaching the lungs.

U.S. Patent publication 2006/0120968 by Niven et al. describes theconcomitant delivery of positive pressure ventilation and activeaerosolized agents, including pulmonary surfactants. Delivery wasreported to be accomplished through the use of a device and system thatwas designed to improve the flow and direction of aerosols to thepatient interface while substantially avoiding dilution by theventilation gas stream. The system employed an aerosol conditioningchamber and a uniquely-shaped connector for directing the aerosol andthe ventilation gas.

U.S. Pat. No. 7,201,167 to Fink et al., describes a method of treating adisease involving surfactant deficiency or dysfunction by providingaerosolized lung surfactant composition into the gas flow within a CPAPsystem. As shown in FIGS. 1 and 6 of the Fink et al. patent, the aerosolis carried by air coming from a flow generator wherein the aerosol isbeing diluted with the air.

Typically, a constant flow CPAP/ventilator circuit used for breathingsupport consists of an inspiratory arm, a patient interface, anexpiratory arm and a source of positive end expiratory pressure (PEEPvalve or column of water). Currently, aerosol generator manufacturersplace nebulizers within the inspiratory arm of the CPAP/ventilatortubing circuit. This can potentially lead to aerosol dilution anddecrease in aerosol concentration (see U.S. Pat. No. 7,201,167 to Finket al.). Aerosol dilution is caused by much higher flows in theCPAP/ventilator circuit as compared to the peak inspiratory flow (PIF)of treated patients. Placement of the nebulizer between ‘Y’ connectorand endotracheal tube (ET) or other patient interface as proposed byFink et al. [11]account for significant increase in dead space depravingpatient from appropriate ventilation.

To overcome the deficiencies of the prior art, the inventors developed aspecial adaptor which enables sufficient separation of the aerosol flowfrom the ventilation flow maintaining optimized ventilation as well as anovel aerosol delivery system.

All references cited herein are incorporated herein by reference intheir entireties.

BRIEF SUMMARY OF THE INVENTION

One aspect of the invention features a respiratory ventilation adaptoruseful for delivery of an aerosolized active agent to a patient withconcomitant positive pressure ventilation. The adaptor comprises: (a) anaerosol flow channel comprising an aerosol inlet port and a patientinterface port, and defining an aerosol flow path from the aerosol inletport to and through the patient interface port; and (b) a ventilationgas flow channel in fluid communication with the aerosol flow channel,comprising a gas inlet port and a gas outlet port, and defining aventilation gas flow path from the gas inlet port to and through the gasoutlet port; wherein the ventilation gas flow path is at least partiallyoffset from the aerosol flow path and at least partially encircles theaerosol flow path.

The adaptor can further comprise a pressure sensor port. The adaptor mayalso further comprise a valve at the aerosol inlet port. In oneembodiment, the valve is a slit or cross-slit valve. In variousembodiments, the valve is sufficiently flexible to allow introduction ofinstruments, catheters, tubes, or fibers into and through the aerosolflow channel and the patient interface port, while maintaining positiveventilatory pressure. The adaptor may also further comprise a removablecap covering the aerosol inlet port. The adaptor may further comprise aone-way valve at the aerosol outlet port.

In certain embodiments, the aerosol flow channel defines a substantiallystraight aerosol flow path, whereas in other embodiments, the aerosolflow channel defines a curved or angled aerosol flow path. The aerosolflow channel is of substantially the same cross-sectional areathroughout its length, or it can be of greater cross sectional area atthe aerosol inlet port than it is at the patient interface port. Incertain embodiments, the fluid communication between the aerosol flowchannel and the ventilation gas flow channel can be provided by anaperture.

In certain embodiments, the ventilation gas flow channel is adapted toform a chamber that includes the gas inlet port, the gas outlet port andthe patient interface port, wherein the aerosol flow channel iscontained within the chamber and extends from the aerosol inlet port atone end of the chamber, through the chamber to an aerosol outlet portwithin the chamber and recessed from the patient interface port at theopposite end of the chamber, wherein the aerosol flow channel is ofsufficient length to extend beyond the gas inlet and outlet ports. Inparticular embodiments the aerosol outlet port is recessed from thepatient interface port by about 8 millimeters or more. In otherparticular embodiments, the volume within the chamber between theaerosol outlet port and the patient interface port is about 1.4milliliters or more.

Another aspect of the invention features a system for delivery of anaerosolized active agent to a patient with concomitant positive pressureventilation, the system comprising: (a) a positive pressure ventilationcircuit comprising a positive pressure generator for producingpressurized ventilation gas and a delivery means for delivering thepressurized ventilation gas to the patient and for directing exhalationgases from the patient; (b) an aerosol generator for producing theaerosolized active agent; and (c) a patient interface for delivering theventilation gas and the aerosolized active agent to the patient; whereinthe positive pressure ventilation circuit and the aerosol generator areconnected to the patient interface through a respiratory ventilationadaptor comprising: (i) an aerosol flow channel having an aerosol inletport and a patient interface port, and defining an aerosol flow pathfrom the aerosol inlet port to and through the patient interface port;and (ii) a ventilation gas flow channel in fluid communication with theaerosol flow channel, comprising a gas inlet port and a gas outlet port,and defining a ventilation gas flow path from the gas inlet port to anthrough the gas outlet port; wherein the ventilation gas flow path is atleast partially offset from the aerosol flow path and at least partiallyencircles the aerosol flow path.

The adaptor may further comprise a pressure sensor port connected to apressure sensor, as well as a valve at the aerosol inlet port. Inembodiments of the system, connection of the aerosol generator to theadaptor causes the valve to open, and disconnection of the aerosolgenerator from the adaptor causes the valve to close. In certainembodiments, the valve, when closed, is sufficiently flexible to allowintroduction of instruments, catheters, tubes, or fibers into andthrough the aerosol flow channel and the patient interface port, whilemaintaining positive ventilatory pressure. The system may furthercomprise an adaptor with a removable cap for the aerosol inlet port, foruse when the aerosol generator is disconnected from the adaptor. Incertain embodiments, the patient interface is not invasive, e.g., is amask or nasal prongs. In other embodiments, the patient interface isinvasive, e.g., an endotracheal tube.

Another aspect of the invention relates to a system for delivery of apropelled aerosolized active agent with concomitant positive pressureventilation to a patient in need of pulmonary lung surfactant, thesystem comprising: a) a positive pressure ventilation circuit comprisinga positive pressure generator for producing pressurized ventilation gasand a delivery conduit for delivering the pressurized ventilation gas tothe patient and for directing exhalation gases from the patient; b) anaerosol generator for producing an aerosolized active agent; c) apatient interface for delivering the ventilation gas and the aerosolizedactive agent to the patient; d) a respiratory ventilation adaptor incommunication with the positive pressure ventilation circuit, theaerosol generator and the patient interface; e) an aerosol entrainmentchamber to produce the propelled aerosolized active agent, wherein theaerosol entrainment chamber is in communication with the aerosolgenerator; and f) an auxiliary circuit in connection with the deliveryconduit for delivering the pressurized ventilation gas to the patient,wherein the auxiliary circuit comprises a first auxiliary conduitconnecting the delivery conduit and the aerosol entrainment chamber anda second auxiliary conduit connecting the aerosol entrainment chamberand the respiratory ventilation adaptor, wherein the first auxiliaryconduit is adapted to accommodate a portion of the pressurizedventilation gas which is removed from a main flow of the pressurizedventilation gas directed toward the respiratory ventilation adaptor, andto enable delivery of the portion of the pressurized ventilation gas tothe aerosol entrainment chamber for combining with the aerosolizedactive agent to form the propelled aerosolized active agent and thesecond auxiliary conduit is adapted to enable delivery of the propelledaerosolized active agent to the respiratory ventilation adaptor.

Yet another aspect of the invention relates to a method of delivery of apropelled aerosolized active agent with concomitant positive pressureventilation to a patient, the method comprising: a) providing a positivepressure ventilation circuit comprising a positive pressure generatorfor producing pressurized ventilation gas and a delivery conduit fordelivering the pressurized ventilation gas to the patient and fordirecting exhalation gases from the patient; b) providing an aerosolgenerator for producing an aerosolized active agent; c) providing apatient interface for delivering the ventilation gas and the aerosolizedactive agent to the patient; d) providing a respiratory ventilationadaptor in communication with the positive pressure ventilation circuit,the aerosol generator and the patient interface; e) providing an aerosolentrainment chamber in communication with the aerosol generator;providing an auxiliary circuit in connection with the delivery conduitfor delivering the pressurized ventilation gas to the patient, whereinthe auxiliary circuit comprises a first auxiliary conduit connecting thedelivery conduit and the aerosol entrainment chamber and a secondauxiliary conduit connecting the aerosol entrainment chamber and therespiratory ventilation adaptor; g) removing a portion of thepressurized ventilation gas from a main flow of the pressurizedventilation gas directed toward the respiratory ventilation adaptor tothe first auxiliary conduit and directing the portion of the pressurizedventilation gas to the aerosol entrainment chamber and thereby combiningthe portion with the aerosolized active agent to form a propelledaerosolized active agent; h) directing the propelled aerosolized activeagent to the second auxiliary conduit and thereby deliver the propelledaerosolized active agent to the respiratory ventilation adaptor; and i)providing the propelled aerosolized active agent and the pressurizedventilation gas to the patient interface and thereby deliver theventilation gas and the propelled aerosolized active agent to thepatient.

Yet another aspect of the invention is an improvement to a method ofdelivery of an aerosolized active agent with concomitant positivepressure ventilation to a patient in need of pulmonary lung surfactant,the improvement comprising diverting a portion of pressurizedventilation gas directed to the patient to be combined with aconcentrated aerosolized active agent in a chamber and using the portionof the pressurized ventilation gas as a carrier (sheath) gas fordelivery of the aerosolized active agent to the patient.

Yet another aspect of the invention is a method for delivering anaerosolized active agent to a patient with concomitant positive pressureventilation, the method comprising: a) providing a positive pressureventilation circuit comprising a positive pressure generator forproducing a pressurized ventilation gas and a delivery conduit fordelivering an amount of the pressurized ventilation gas to the patientand for directing a flow of exhalation gas from the patient; b)providing an aerosol generator for producing the aerosolized activeagent; c) providing a patient interface for delivering the ventilationgas, the aerosolized active agent or the mixture thereof to the patient;d) connecting the positive pressure ventilation circuit and the aerosolgenerator to the patient interface through an adaptor, the adaptorcomprising: i) an aerosol flow channel having an aerosol inlet port anda patient interface port, and defining an aerosol flow path from theaerosol inlet port to and through the patient interface port; and ii) aventilation gas flow channel in fluid communication with the aerosolflow channel and having a gas inlet port and a gas outlet port, anddefining a ventilation gas flow path from the gas inlet port to andthrough the gas outlet port, wherein the ventilation gas flow path is atleast partially offset from the aerosol flow path and at least partiallyencircles the aerosol flow path; e) providing the pressurizedventilation gas to the patient, wherein the volume of the pressurizedventilation gas is regulated by at least one of the length of theaerosol flow channel and the pressure created by an increased demand forair which is not matched by the aerosol flow; and f) providing anaerosol flow of the aerosolized active agent to a chamber inside theadaptor such that aerosol flow is introduced below the ventilation gasflow channel wherein the aerosol flow is selected to match the patient'sinspiratory flow and thereby providing the aerosolized active agent tothe patient. Other features and advantages of the invention will beunderstood by reference to the drawings, detailed description andexamples that follow.

BRIEF DESCRIPTION OF SEVERAL VIEWS OF THE DRAWINGS

FIG. 1A is an isometric view of an embodiment of the adaptor of thepresent invention.

FIGS. 1B and 1C are isometric views of alternative embodiments of theadaptor.

FIG. 2A is a plan view of the front of the adaptor of FIG. 1A.

FIG. 2B is a section view of the adaptor of FIG. 2A, as seen along line2B-2B.

FIG. 2C is a section view of the adaptor of FIG. 2A as seen along line2B-2B, showing an alternative internal configuration.

FIG. 2D is a section view of the adaptor of FIG. 2A, as seen along line2D-2D.

FIG. 3 is an isometric section view of a portion of the adaptor of FIG.1A.

FIG. 4 is another isometric section view of another portion of theadaptor of FIG. 1A.

FIG. 5A is an isometric view of another embodiment of the adaptor of thepresent invention.

FIGS. 5B and 5C are isometric views of alternative embodiments of theadaptor.

FIG. 6 is a top view of the adaptor shown in FIG. 5B.

FIG. 7 is a plan view of the front of the adaptor of FIG. 5B.

FIG. 8 illustrates a ventilatory circuit including an adaptor of thetype shown in FIG. 1A, 1B, or 1C.

FIG. 9 is a schematic diagram illustrating a proximal aerosol deliverysystem (PADS).

FIG. 10 a schematic diagram illustrating another embodiment of aproximal aerosol delivery system (PADS) suitable for delivery ofmultiple substances.

FIG. 11 a schematic diagram illustrating another embodiment of aproximal aerosol delivery system (PADS) suitable for delivery ofmultiple substances.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS OF THE INVENTION

The present invention provides, inter alia, devices and systems forpulmonary delivery of one or more aerosolized active agents to apatient, concomitantly with administration of noninvasive or invasiveventilatory support.

Unless otherwise indicated the terminology used herein is for thepurpose of describing particular embodiments only and is not intended tolimit the scope of the present invention. It must be noted that as usedherein and in the claims, the singular forms “a,” “and” and “the”include plural referents unless the context clearly dictates otherwise.

“About” as used herein when referring to a measurable value such as anamount, a temporal duration, and the like, is meant to encompassvariations of ±20% or ±10%, more preferably ±5%, even more preferably±1%, and still more preferably ±0.1% from the specified value, as suchvariations are appropriate to perform the disclosed methods.

The term “active agent” as used herein refers to a substance orcombination of substances or devices that can be used for therapeuticpurposes (e.g., a drug), diagnostic purposes or prophylactic purposesvia pulmonary delivery. For example, an active agent can be useful fordiagnosing the presence or absence of a disease or a condition in apatient and/or for the treatment of a disease or condition in a patient.Certain “active agents” are substances or combinations of substancesthat are capable of exerting a biological effect when delivered bypulmonary routes. The bioactive agents can be neutral, positively ornegatively charged. Exemplary agents include, for example, insulins,autocoids, antimicrobials, antipyretics, antiinflammatories,surfactants, antibodies, antifungals, antibacterials, analgesics,anorectics, antiarthritics, antispasmodics, antidepressants,antipsychotics, antiepileptics, antimalarials, antiprotozoals, anti-goutagents, tranquilizers, anxiolytics, narcotic antagonists,antiparkinsonisms, cholinergic agonists, antithyroid agents,antioxidants, antineoplastics, antivirals, appetite suppressants,antiemetics, anticholinergics, antihistaminics, antimigraines, bonemodulating agents, bronchodilators and anti-asthma drugs, chelators,antidotes and antagonists, contrast media, corticosteroids, mucolytics,cough suppressants and nasal decongestants, lipid regulating drugs,general anesthetics, local anesthetics, muscle relaxants, nutritionalagents, parasympathomimetics, prostaglandins, radio-pharmaceuticals,diuretics, antiarrhythmics, antiemetics, immunomodulators,hematopoietics, anticoagulants and thrombolytics, coronary, cerebral orperipheral vasodilators, hormones, contraceptives, diuretics,antihypertensives, cardiovascular agents such as cardiotonic agents,narcotics, vitamins, vaccines, and the like.

In one embodiment, the active agent employed is a high-dose therapeutic.Such high dose therapeutics would include antibiotics, such as amikacin,gentamicin, colistin, tobramycin, amphotericin B. Others would includemucolytic agents such as N-acetylcysteine, Nacystelyn, alginase,mercaptoethanol and the like. Antiviral agents such as ribavirin,gancyclovir, and the like, diamidines such as pentamidine and the likeand proteins such as antibodies are also contemplated.

A preferred active agent is a substance or combination of substancesthat is used for pulmonary prophylactic or rescue therapy, such as apulmonary surfactant (PS).

Natural PS lines the alveolar epithelium of mature mammalian lungs.Natural PS has been described as a “lipoprotein complex” because itcontains both phospholipids and apoproteins that act in conjunction tomodulate the surface tension at the lung air-liquid interface andstabilize the alveoli to prevent their collapse. Four proteins have beenfound to be associated with pulmonary surfactant, namely SP-A, SP-B,SP-C, and SP-D (Ma et al., Biophysical Journal 1998, 74:1899-1907).Specifically, SP-B appears to impart the full biophysical properties ofpulmonary surfactant when associated with the appropriate lung lipids.An absence of SP-B is associated with respiratory failure at birth.SP-A, SP-B, SP-C, and SP-D are cationic peptides that can be derivedfrom animal sources or synthetically. When an animal-derived surfactantis employed, the PS is often bovine or porcine derived.

For use herein, the term PS refers to both naturally occurring andsynthetic pulmonary surfactant. Synthetic PS, as used herein, refers toboth protein-free pulmonary surfactants and pulmonary surfactantscomprising synthetic peptides or peptide mimetics of naturally occurringsurfactant protein. Any PS currently in use, or hereafter developed foruse in RDS and other pulmonary conditions, is suitable for use in thepresent invention. Exemplary PS products include, but are not limitedto, lucinactant (Surfaxin®, Discovery Laboratories, Inc., Warrington,Pa.), poractant alfa (Curosurf®, Chiesi Farmaceutici SpA, Parma, Italy),beractant (Survanta®, Abbott Laboratories, Inc., Abbott Park, Ill.) andcolfosceril palmitate (Exosurf®, GlaxoSmithKline, PLC, Middlesex, U.K.).

While the methods and systems of this invention contemplate use ofactive agents, such as pulmonary surfactant compositions, antibiotics,antivirals, mucolytic agents, as described above, the preferred activeagent is a synthetic pulmonary surfactant. From a pharmacological pointof view, the optimal exogenous PS to use in the treatment would becompletely synthesized in the laboratory. In this regard, one mimetic ofSP-B that has found to be useful is KL4, which is a 21 amino acidcationic peptide. Specifically the KL4 peptide enables rapid surfacetension modulation and helps stabilize compressed phospholipidmonolayers. KL4 is representative of a family of PS mimetic peptideswhich are described for example in U.S. Pat. Nos. 5,260,273 and5,407,914. Preferably, the peptide is present within an aqueousdispersion of phospholipids and free fatty acids or fatty alcohols,e.g., DPPC (dipalmitoyl phosphatidylcholine) and POPG (palmitoyl-oleylphosphatidylglycerol) and palmitic acid (PA). See, for example, U.S.Pat. No. 5,789,381.

As used herein, the term “aerosol” refers to liquid or solid particlesthat are suspended in a gas. Typically, the “aerosol” or “aerosolizedagent” referred to herein contains one or more of the active agents, asreferred to above. The aerosol can be in the form of a solution,suspension, emulsion, powder, solid, or semi-solid preparation.

The term “ventilation” or “respiratory ventilation” as used hereinrefers to mechanical or artificial support of a patient's breathing. Theprinciples of mechanical ventilation are governed by the Equation ofMotion, which states that the amount of pressure required to inflate thelungs depends upon resistance, compliance, tidal volume and inspiratoryflow. The principles of mechanical ventilation are described in detailin Hess and Kacmarek, ESSENTIALS OF MECHANICAL VENTILATION, 2^(nd)Edition, McGraw-Hill Companies (2002). The overall goals of mechanicalventilation are to optimize gas exchange, patient work of breathing andpatient comfort while minimizing ventilator-induced lung injury.Mechanical ventilation can be delivered via positive-pressure breaths ornegative-pressure breaths. Additionally, the positive-pressure breathscan be delivered noninvasively or invasively.

Noninvasive mechanical ventilation (NIMV) generally refers to the use ofa mask or nasal prongs to provide ventilatory support through apatient's nose and/or mouth. The most commonly used interfaces fornoninvasive positive pressure ventilation are nasal prongs,nasopharyngeal tubes, masks, or oronasal masks. Desirable features of amask for noninvasive ventilation include low dead space, transparent,lightweight, easy to secure, adequate seal with low facial pressure,disposable or easy to clean, nonirritating to the skin (non-allergenic)and inexpensive.

NIMV is distinguished from those invasive mechanical ventilatorytechniques that bypass the patient's upper airway with an artificialairway (endotracheal tube, laryngeal mask airway or tracheostomy tube).NIMV can be provided by either bi-level pressure support (so called“BI-PAP”) or continuous positive airway pressure (CPAP). Bi-levelsupport provides an inspiratory positive airway pressure for ventilatoryassistance and lung recruitment, and an expiratory positive airwaypressure to help recruit lung volume and, more importantly, to maintainadequate lung expansion. Continuous positive airway pressure provides asingle level of airway pressure, which is maintained above atmosphericpressure throughout the respiratory cycle. For a further review ofinvasive and noninvasive mechanical ventilation, see Cheifetz, I. M.,Respiratory Care, 2003, 48:442-453.

The employment of mechanical ventilation, whether invasive ornon-invasive, involves the use of various respiratory gases, as would beappreciated by the skilled artisan. Respiratory gases pulmonaryrespiratory therapy are sometimes referred to herein as “CPAP gas,”“ventilation gas,” “ventilation air,” or simply “air.” However, thoseterms are intended to include any type of gas normally used forrespiratory therapy. The terms “channel” and “chamber” are usedinterchangeably in this disclosure and are not intended to be limited toany particular shape or form.

The term “a delivery means” when used together with ventilation gasrefer to a conduit or a network of conduits containing (if needed)various devices (pressure valves, sensors, etc.) necessary to enabledelivery of ventilation gas, preferably pressurized ventilation gas, toand from the adaptor. The type of conduits, their geometry and materialsthey are made of are not limited to any specifics. A person skilled inthe art should be able to select appropriate conduits and devices basedon the teaching disclosed herein and knowledge available in the art.

Turning now to the drawings, FIG. 1A shows an embodiment of theventilation circuit adaptor 10 including a body 15, an aerosol flowchamber 17 and a ventilation gas flow chamber 18. The aerosol flowchamber 17 comprises an aerosol inlet port 14 with an optional valve(not visible) and a patient interface port 16. As shown in FIG. 2B,aerosol is passed from an aerosol generator (not shown) directly orindirectly (e.g., via tubing) through the aerosol inlet port 14 into theaerosol flow channel 12 and out of the aerosol flow channel 12 to thepatient via the aerosol outlet port 30 to and through the patientinterface port 16. The patient interface port 16 is connected directlyor indirectly (e.g., via tubing) to a patient interface, such as anendotracheal tube, a mask or nasal prongs (not shown). As shown in FIG.1A, the ventilation gas flow chamber 18 comprises ventilation gas inletand outlet ports 20 and 22, respectively. It is understood that theinlet and the outlet can be switched such that the inlet can become anoutlet and the outlet can become the inlet. In this embodiment, theventilation gas flow chamber 18 is joined with the aerosol flow chamber17 to facilitate flow of the aerosol without dilution with ventilationgas or with a minimum dilution as shown more fully in FIGS. 2A-4. Thebody 15 further comprises an optional pressure sensor port 24. While themain body of the adaptor 10 is preferably roughly cylindrical along itslength, it will be appreciated by one of skill in the art that the bodyof the adaptor 10 may utilize any cross-sectional shape.

FIGS. 1B and 1C illustrate alternative embodiments of the adaptor shownin FIG. 1A. FIG. 1B shows an angled configuration; FIG. 1C shows acurved configuration.

FIGS. 2A-2D illustrate the embodiment of the adaptor shown in FIG. 1A inmore detail. As seen in FIG. 2A, the ventilation gas flow chamber 18 isjoined with an aerosol flow chamber 17 to form a combined body 15 whichhouses a chamber 28 (as illustrated in FIGS. 2B, 2C, and 4). The aerosolflow channel 12 is nested within the chamber 28. As shown in FIG. 2B,the aerosol 21 is introduced into the aerosol flow channel 12 viaaerosol inlet port 14, through valve 26. The aerosol 21 flows throughthe aerosol flow channel 12 to and through the aerosol outlet port 30,then to and through the patient interface port 16. The length L1 of theaerosol flow channel 12 is sufficient to extend beyond the ventilationgas flow chamber 18, but is recessed within the chamber 28 by a lengthL2 to minimize resistance arising from the patient's exhalations. Theinventors have discovered that selecting the proper value for L1 has adirect impact on the volume of ventilation gas which reaches the patientinterface port. Ventilation gas 23 is introduced through gas inlet port20 into a ventilation gas flow channel 19 (shown in FIG. 2D) and followsa flow path that partially encircles the aerosol flow channel 12, butmay be pulled toward the patient interface port 16 under certaincircumstances (e.g., when aerosol flow is not being generated or whenthe aerosol flow rate is less than the patient's inspiratory flow (PIF)as indicated by “broken lines” in FIGS. 2B and 2C). As shown in FIG. 2B,the aerosol flow channel 12 occupies the entire volume of the aerosolflow chamber 17 at the portion near the aerosol inlet port 14 and abovethe ventilation gas flow chamber 18, then narrows between theventilation gas flow chamber 18 and the aerosol outlet port 30 and thuscreating a separation barrier between the aerosol flow and theventilator flow, to enable the ventilation gas flow chamber 18 to atleast partially encircle the aerosol flow channel 12. The separationbarrier between the aerosol flow and the ventilator flow has apredetermined length L1. The inventors have discovered that introducingthe aerosol to the chamber 28 at a point below the ventilation gas flowchannel prevents high ventilatory flow rates from diluting the aerosolor at least decreases the aerosol dilution effect, thus allowing more ofthe aerosol to reach the patient interface. In order to maximize aerosolinhaled dose and decrease aerosol losses, the aerosol flow is selectedto match the PIF. Nevertheless, ventilator flow rates are alwayssignificantly higher than PIF. Thus, by separation of aerosol flow fromhigher ventilator flows, aerosol dilution, which occurs whenever aerosolflow is introduced directly to the ventilatory flow path, can be avoidedor minimized. Using the adaptor of the invention, the amount of theventilation gas delivered to the patient can be regulated by selectingthe length of the aerosol flow channel and/or regulating the pressurecreated by an increased demand for air which is not matched by theaerosol flow (e.g., when PIF is higher than the aerosol flow rate).

As shown in FIG. 2B, the aerosol flow channel 12 forms a funnel-likeshape. This arrangement minimizes corners, and thus helps to prevent theaccumulation of deposits within the adaptor. In an alternativeembodiment shown in FIG. 2C, the aerosol flow channel 12 issubstantially the same diameter throughout its length, and is notconfigured as a funnel. In either embodiment, the aerosol flow channel12 is sufficiently narrower than the chamber 28 to allow for flow ofventilation gas 23 around the aerosol flow channel 12.

FIGS. 2D and 3 show the arrangement of the ventilation gas inlet andoutlet ports 20/22 and the optional pressure sensor port 24, and theflow of ventilation gas around the aerosol flow channel 12. Ventilationgas flows into the ventilation gas flow channel 19 through port 20 andout through port 22, with a portion being pulled toward the patientinterface port 16 through the chamber 28, substantially parallel to theaerosol flow path 21, under certain circumstances (e.g., when aerosolflow is not being generated or when the aerosol flow rate is less thanthe patient's inspiratory flow).

FIG. 4 illustrates the arrangement of the aerosol inlet port at the topof the adaptor. A removable cap 32 is shown. The cap 32 may be utilizedwhen the aerosol generator is not being used, and removed when theadaptor is connected to an aerosol generator. The aerosol flows throughvalve 26 into the aerosol flow channel 12. The valve 26 is preferably aslit or cross-slit valve of the type known in the art. When an aerosolgenerator is attached to the adaptor, the valve 26 is forced into anopen position. When the aerosol generator is removed, the valve 26closes. The adaptor 10 may further comprise a one-way valve 34 at theaerosol outlet port 30, to reduce or prevent any reverse aerosol flowsthat might occur during excessive expirations. A security lock 35 isused to prevent dislocation of valve 26.

FIG. 5A shows another embodiment of the ventilation circuit adaptor 110,which includes an aerosol flow channel 112 and a ventilation gas flowchannel 118. Similarly to the adaptor shown in FIGS. 1A-4, the aerosolflow channel 112 comprises an aerosol inlet port 114 with an optionalvalve (not visible) and a patient interface port 116. The ventilationgas flow channel 118 comprises ventilation gas inlet and outlet ports 20and 22, respectively. In this embodiment, the ventilation gas flowchannel is not adapted to form a chamber through which passes theaerosol flow channel. Instead, the aerosol flow channel 112 and theventilation gas flow channel 118 are formed as substantially separatedtubes, in fluid communication by means of an aperture 36 (shown in FIG.7). In the embodiment shown, the optional pressure sensor port 24 isplaced in the aerosol flow channel 112, near the patient interface.While the two flow channels are roughly tubular in shape, it will beappreciated by one of skill in the art that either or both channels maybe of any cross-sectional dimension.

FIGS. 5B and 5C illustrate alternative embodiments of the adaptor shownin FIG. 5A. FIG. 5B shows a straight configuration for the aerosol flowchannel 112; FIG. 5C shows an angled configuration for the aerosol flowchannel 112.

FIG. 6 and FIG. 7 illustrate the embodiment of the adaptor shown in FIG.5B viewed from different angles. As seen in the top view of FIG. 6 andthe front view of FIG. 7, the ventilation gas flow channel 118 issubstantially separated from the aerosol flow channel 112, and is influid communication therewith by means of an aperture 36. Aerosol isintroduced into the aerosol flow channel 112 via aerosol inlet port 114,through optional valve 126 (not shown). The aerosol flows through theaerosol flow channel 112 to and through the patient interface port 116.Ventilation gas is introduced through gas inlet port 20 and follows aflow path that partially encircles the aerosol flow channel and exits atgas outlet port 22, but may move through the aperture 36 into theaerosol flow channel 112, toward the patient interface port 116 undercertain circumstances (e.g., when aerosol flow is not being generated orwhen the aerosol flow rate is less than the patient's inspiratory flow).

FIG. 8 depicts the arrangement of the adaptor 10 and various ventilatoryand aerosol tubes of a system of the invention, as it may be used in aneonatal setting. It is understood that the adaptor can be used in anysetting or with any apparatus suitable for pulmonary aerosol delivery.Tube 38 from the aerosol generator (generator not shown) is attached tothe aerosol inlet port 14 of the adaptor 10. Ventilation gas inlet port20 and outlet port 22 are affixed, respectively to tubes 40 and 42,which form the ventilatory circuit that includes the positive pressuregenerator (not shown). The pressure sensor port 24 (not shown) isattached via tubing 44 to a pressure sensor (pressure sensor not shown).The patient 46 is administered respiratory therapy through a patientinterface, such as, for example, an endotracheal tube 48 which isaffixed to the patient interface port 16.

The ventilation circuit adaptor of the present invention may be formedof, for example, polycarbonate or any other suitable material; however,materials such as molded plastic and the like, of a type used for tubingconnectors in typical ventilatory circuits, are particularly suitable.The material utilized should be amenable to sterilization by one or morestandard means. In certain embodiments, the adaptor is made ofdisposable materials. In certain embodiments, the adaptor is made ofmaterials capable of withstanding temperatures and pressures suitablefor sterilizing.

The adaptor may be of any size or shape within the functional parametersset forth herein. In a preferred embodiment, the adaptor is of a sizeand shape that enables its use with standard tubing and equipment usedin mechanical ventilation circuits. This is of particular advantage overcertain previously disclosed connectors (e.g., U.S. patent publication2006/0120968 to Niven et al.), wherein the size of the chamber accountsfor significant ventilation dead space, minimizing its effective use ininvasive mechanical ventilation applications or other connectors (e.g.,U.S. Pat. No. 7,201,167 to Fink et al.), wherein the aerosol is dilutedwith the ventilation gas. In particular embodiments, the adaptor isdesigned to replace the typical “Y” or “T” connector used in ventilatorycircuits, and its size is such that no additional ventilation dead spaceis introduced into the ventilatory circuit. However, custom sizes andshapes may easily be fabricated to accommodate custom devices orequipment, as needed.

The ventilation circuit adaptor can comprise one or more optionalfeatures, either singly or in combination. These include: (1) one ormore ports for attaching monitoring equipment, such as a pressuresensor; (2) a valve at the aerosol inlet port; (3) a removable cap forthe aerosol inlet port; (4) a one-way valve at the aerosol outlet port;and (5) a temperature probe.

The port(s) for attaching monitoring equipment can be placed in variouspositions on the adaptor, as dictated by use with standard or customequipment and in keeping with the intended function of the port. Forinstance, a pressure sensor port should be positioned on the adaptorsuch that ventilation and/or aerosol flow pressure can be accuratelymeasured.

The valve at the aerosol inlet port is a particularly useful optionalfeature of the adaptor. Particularly suitable valves include slit orcross-slit valves. The valve is forced into an open position byattachment of an aerosol generator tube or the aerosol generator itself,and returns to a closed position when the aerosol generator tube isdisconnected. As would be readily appreciated by the skilled artisan,the valve should be fabricated of material that is sufficiently flexibleand resilient to enable to valve to return to a substantially closed,sealed position when the aerosol generator is disconnected. Thus, thevalve at the aerosol inlet port enables a substantially constantpressure to be maintained within the ventilatory circuit even when theaerosol generator is not attached to the adaptor. Advantageously, thepresence of the valve and resultant ability to maintain substantiallyconstant positive pressure, enables the adaptor to serve as a point ofaccess, allowing safe application of catheters or surgical anddiagnostic devices such as fiberoptic scopes to patients underventilatory support, without interrupting such breathing support. Thecatheters may be cleaning catheters used to clean the upper or lowerairways, nebulizing catheters to deliver aerosolized drugs as well asother substances or conduits to deliver liquid drugs as well as othersubstances to the airways. The adaptor can also include a removable capto seal the aerosol inlet port when the port is not in use.

In certain embodiments, the adaptor can further include a one-way valveat the aerosol outlet port. The one-way valve can be fabricated offlexible, resilient material that may be the same or different from thematerial used to fabricate the valve at the aerosol inlet port. Theone-way valve at the aerosol outlet port can be included to reduce orprevent any reverse aerosol flow that might occur during excessiveexpirations.

In certain embodiments, some of which are depicted in FIGS. 1A-4, theventilation gas flow channel is adapted to form a chamber through whichpasses the aerosol flow channel. In such embodiments, the walls definingthe aerosol flow channel extend beyond the ventilation gas flow channelas defined by the ventilation gas inlet and outlet ports. However, thelength of the aerosol flow channel is also such that the aerosol outletport is recessed from the patient interface port, so as to reduce therisk or incidence of expiratory resistance during controlled mechanicalventilation (CMV) or intermittent mechanical ventilation (IMV). Incertain embodiments designed for neonatal use, the aerosol outlet portis recessed from the patient interface port by at least about 8millimeters (L2, FIG. 2B), with the chamber volume in the recess beingat least about 1.4 milliliters. In certain embodiments designed forolder infants, children or adults, the aerosol outlet port can befurther recessed from the patient interface port, e.g., by at leastabout 9, 10, 11, 12, 13, 14, 15 or 16 millimeters, with concomitantlyincreased chamber volume in the recess, e.g., at least about 1.5, 1.6,1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9 or 3.0milliliters.

The ventilatory circuit adaptor of the present invention can be madefrom any material suitable for the delivery of the substances describedherein, e.g., polymers, metals, or composite materials. It is preferredthat the materials are capable of being sterilized. The adaptors can bemanufactured by methods known in the art, such as, for example,injection molding.

The ventilatory circuit adaptor of the present invention can be used inany ventilatory circuit to adapt it for use with an aerosol generator.The aerosol generator is introduced into the circuit via the adaptor.The aerosol generator may be directly or indirectly connected to theadaptor, e.g., via tubing, as would be understood by the skilledartisan. Any type of nebulizer or aerosol generator may be used. Forinstance, the aerosol generator can be an ultrasonic nebulizer orvibrating membrane nebulizer or vibrating screen nebulizer. Typically,jet nebulizers are not employed although the present methods can beadapted to all types of nebulizers or atomizers. In one embodiment, theaerosol generator is an Aeroneb® Professional Nebulizer (Aerogen Inc.,Mountain View, Calif., USA). In another embodiment, the aerosolgenerator is a capillary aerosol generator, an example of which is asoft-mist generator by Philip Morris USA, Inc. Richmond, Va. (see U.S.Pat. Nos. 5,743,251 and 7,040,314; T. T. Nguyen, K. A. Cox, M. Parkerand S. Pham (2003) Generation and Characterization of Soft-Mist Aerosolsfrom Aqueous Formulations Using the Capillary Aerosol Generator, J.Aerosol Med. 16:189).

In certain embodiments, the adaptor can be used with a conduit insertedinto the aerosol inlet port, through the aerosol flow channel and outthe patient interface directly into the patient's nose (e.g., via nasalprongs or nasal tube) or mouth (e.g., via endotracheal tube) such thatan active agent is provided in a liquid form or an aerosol form via theconduit.

The ventilation circuit further comprises a patient interface, which isselected to accommodate the type of ventilatory support to beadministered. Invasive applications such as controlled, assisted orintermittent mandatory ventilation will utilize an endotracheal ortracheostomy tube as the patient interface. Non-invasive applicationssuch as CPAP or BI-PAP may utilize nasal prongs or nasopharyngeal tubes,or a mask that covers the nose or both the nose and mouth, as thepatient interface. In certain embodiments, the patient interface isconnected directly to the adaptor. In other embodiments, a length oftubing may be introduced between the adaptor and the patient interface.

Thus, in practice, the system of the invention is utilized byestablishing the patient on respiratory ventilation utilizing a circuitthat includes the adaptor, introducing one or more active agents intothe aerosol generator attached to the adaptor, and delivering to thepatient through the adaptor a flow of the aerosolized active agent. Theactual dosage of active agents will of course vary according to factorssuch as the extent of exposure and particular status of the subject(e.g., the subject's age, size, fitness, extent of symptoms,susceptibility factors, and the like). By “effective dose” herein ismeant a dose that produces effects for which it is administered. Theexact dose will be ascertainable by one skilled in the art using knowntechniques. In one exemplary embodiment, the effective dose of pulmonarysurfactant for delivery to a patient by the present methods will be fromabout 2 mg/kg surfactant total phospholipid (TPL) to about 175 mg/kgsurfactant TPL. The length of treatment time will also be ascertainableby one skilled in the art and will depend on dose administered anddelivery rate of the active agent. For example, in embodiments whereinthe delivery rate of aerosol to a patient is about 0.6 mg/min, greaterthan 100 mg of aerosol can be delivered in less than a 3 hour timeframe. It will be understood by the skilled practitioner that a lowerdelivery rate will correspond to longer administration times and ahigher delivery rate will correspond to shorter times. Similarly, achange in dose will affect treatment time.

Another aspect of the invention is an improvement in a method ofdelivery of an aerosolized active agent with concomitant positivepressure ventilation to a patient, wherein the improvement comprisesdiverting a portion of pressurized ventilation gas directed to thepatient and combining it with a concentrated aerosolized active agent ina chamber and using the portion of the pressurized ventilation gas as acarrier (sheath) gas for delivery of the aerosolized active agent to thepatient, thereby creating an auxiliary circuit for a carrier gas andaerosol delivery to a patient. It should be understood that theauxiliary circuit described in detail below can be used with any deviceor adaptor which enables delivery of a combination of a ventilation airand aerosol flows to a patient.

In yet another embodiment, the adaptor of the invention can be used in anovel aerosol delivery system. The combination of the adapter and theventilation circuit described above creates a Proximal Aerosol DeliverySystem (PADS) 100 as exemplified in FIGS. 9-11. In the PADS, anauxiliary circuit is created for diverting a portion of the inspiratoryventilation flow to the aerosol entrainment chamber (AEC) to be used asa carrier or sheath gas for delivery of aerosolized active agent to theregulator. Advantageously, the AEC collects a concentrated aerosolizedactive agent which is then diluted with the sheath gas to the desiredconcentration. Thus, the sheath gas plays a dual role as a transporterand a diluent of the aerosolized active agent.

PADS 100 comprises an inspiratory arm 40 equipped with a T-connector 39.The T-connector 39 allows directing a predetermined portion of the flowfrom the ventilation circuit to the sheath gas tube 51. The amount ofthe ventilation air diverted to the sheath gas tube 51 is selected basedon patient's PIF (2-5 L/min for newborns, 6-20 L/min for pediatricpopulation and 20-30 L/min for adults). The sheath gas tube 51 has aflow restrictor 50. The sheath gas tube 51 with the flow restrictor 50assures delivery of appropriate air flow to an aerosol entrainmentchamber (AEC) 52. The sheath gas flow is equal to or higher than thepatient's PIF and is regulated by a flow restrictor. The sheath gas flowis preferably within the range of 2-5 L/min for neonatal population andrespectively higher for pediatric (e.g., 6-20 L/min) and adultpopulations (e.g., 20-60 L/min). In another variant, a built-in air flowregulator can be used in place of a flow restrictor for adjusting thesheath gas flow. In such case, the built-in air flow regulator islocated in the AEC.

The sheath gas tube 51 can be connected to the inspiratory arm 40 of theventilation circuit before or after a heater/humidifier (not shown). Theplacement of the sheath gas tube connector depends on the type ofaerosol delivered to the patient. If the aerosol generated by thenebulizer is relatively dry and there is a risk for particles growth inthe humidified environment, the sheath gas tube connector will be placedbefore the heater/humidifier. If the aerosol generated by the nebulizeris relatively wet and there is not a risk for additional particlesgrowth in the humidified environment, the sheath gas connector can beplaced after the heater/humidifier.

The inspiratory arm 40 is adapted to deliver the balance of theventilation flow 23 to the adaptor 10 via the inspiratory flow port 20as described above.

PADS 100 also comprises an expiratory arm 42 equipped with an exhalationfilter (not shown). The exhalation filter has satisfactory capacity inorder to prevent aerosol from reaching a PEEP valve and/or ambient airin the ‘bubble CPAP’ circuit set-up. The expiratory arm 42 is connectedwith the adaptor 10 via the expiratory flow port 22 and is adapted toremove ventilation air flow 23 from the adaptor 10.

The adaptor 10 (or 110) is connected to the inspiratory arm 40, and theexpiratory arm 42 via inspiratory flow port 20 and expiratory flow port22 respectively. The adaptor assures appropriate separation ofventilator flows directing undiluted aerosol towards patient.

The purpose of the AEC 52 is to provide maximal aerosol entrainment andhigh aerosol concentration to the adaptor 10. The AEC 52 may have abuilt-in flow regulator for sheath gas flow adjustment.

An aerosol generator 55 is located proximate to or connected with theAEC 52. It should be understood that any type of aerosol generatorincluding, for example, mesh vibrating, jet or capillary aerosolgenerators, can be used in this invention.

A drug reservoir 56 is connected with the aerosol generator 55 by meansof a drug feeding line 57. The drug reservoir 56 and the feeding lineassure drug supply to the aerosol generator, whenever nebulization isrequired including continuous supply. It should be understood thatmultiple drug reservoirs containing different drugs or reservoirscontaining auxiliary substances other than drugs, e.g., pharmaceuticallyacceptable carriers together with multiple feeding lines, can beprovided as needed (see, for example FIG. 11). Also, multiple aerosolgenerators can be used. An exemplary embodiment of such multiple aerosolgenerators is shown in FIG. 10, wherein a first aerosol generator 55 anda second aerosol generator 61 are connected to a drug reservoir 56 viafirst drug feeding line 57 and a second drug feeding line 60respectively. In certain embodiments, the feeding line is eliminated andthe drug reservoir is connected directly with the aerosol generator.

A heating device 59 as shown in FIGS. 9 and 10 is located within thesheath gas tube 51 and is used to heat the sheath gas 58 flowing thoughthe sheath gas tube 51 before the entrance to the AEC 52. The heatingdevice is optional. It can be used for delivery of a heated air/aerosolmixture to a patient. Heating of the sheath gas can also decreasepotential particle growth as the sheath gas is not humidified.

As shown in FIG. 11, two drug reservoirs 56 and 62 are connected viadrug feeding lines 57 and 60 to respective Aerosol Entrainment Chambers52 and 67. The auxiliary circuits are formed via two T-connectors andflow restrictors 50 and 63 allowing diverting a portion of theinspiratory ventilation gas into sheath gas tubes 51 and 64 to arespective AEC 52 and 67 for contacting with the aerosolized drug.Connecting conduits 53 and 68 are connecting each AEC with acorresponding control unit 54 and 69, wherein each control unit can havea free standing or a built-in patient interface. Heating devices 59 and65 are located within the sheath gas tube 51 and 64 respectively. Theaerosol flow 21 is combined at a junction located in the aerosol tube38.

AECs and drug reservoirs can be made of polycarbonate or materials knownin the art suitable for operating at temperatures and pressures in therange of 18-40C.° and 5-60 cm H₂O.

An aerosol tube 38 is adopted to carry an entrained aerosol 21 from theAEC 52 to the aerosol inlet port 14. The length of the aerosol tube 38can be selected to achieve optimal delivery based on the type of aerosoland characteristics of aerosol generators as known in the art. Incertain embodiments, the AEC 52 is connected directly with the port 14without the aerosol tube 38. Any known connector proving an appropriateseal can be used for this purpose In certain embodiments, the length ofaerosol tube 38 does not exceed 20 cm. Preferably, the aerosol tube 38is expandable to secure the optimized placement of the nebulizer, forexample, as close to the patient as possible but in comfortable locationto avoid restriction of any nursing procedures and allow patient forsome head motion. Expandable tubes will help avoid sharp angle creationand thus avoid potential aerosol deposition within the delivery system.

The aerosol tube can be equipped with an optional expandable aerosolreservoir (not shown). This reservoir is a balloon with a volume equalto or as close as possible to a patient's tidal volume and withcompliance equalizing PIF. During inspiration, the patient will bebreathing in aerosol without diluting it as described above, whereasduring exhalation the balloon will refill with aerosol up to the volumeof tidal volume or similar and thus limit the aerosol losses to theexpiratory arm of the circuit. The resistance of the balloon willmaintain desired pressure within the ventilator system. During the phasefollowing inspiration, the patient will inhale optimized highlyconcentrated aerosol from the balloon as it will be pushed away byelastic forces. This system will limit losses of the drug duringexhalation. The size of the balloon depends on the patient's tidalvolume and can differ for particular age groups.

A control unit 54 is located outside a patient bed (not shown). Thecontrol unit 54 has a user interface allowing for input/output ofrelevant information, e.g., patient weight. Any suitable control unitcan be used in this invention. A patient's weight determines PIF whichis matched with sheath gas flow. The control unit 54 is in communicationwith the aerosol generator 55 and the AEC 52 through a wire 53 orwirelessly (e.g., bluetooth technology).

Advantages of PADS as compared to the existing aerosol delivery modelsinclude (a) eliminates aerosol dilution by high ventilator gas flowswithin ventilator circuits, (b) eliminates additional sources for sheathgas flow or aerosol flow, and (c) proximal placement to a patientinterface and thus reduction of potential drug losses within the PADS.Moreover, none of the PADS components increase dead space. Distantlocation of the control unit makes device operations much easier.

PADS can be used with different modes of ventilation including but notlimiting to CPAP, IMV, and synchronized intermittent mechanicalventilation (SIMV). A simple version of PADS without a built-in flowregulator can operate on IMV/SIMV mode based on this same relativeincrease of the sheath gas flow through AEC driven by the increased flowor pressure within the ventilation circuit. Thus, the increased sheathgas flow will deliver more aerosol through the adaptor towards thepatient during inhalation. A more complex version of PADS with abuilt-in flow generator will increase the flow of sheath gas based on amechanism triggered by a patient. Such triggering mechanism can bebased, for example, on Grasbay capsule sensing diaphragm motion orElectric Activity of the Diaphragm (EAdi) [12] which is clinically knownas Neuronal Adjusted Ventilation (NAVA) sensing the phrenic anddiaphragm nerve impulses. In such case the signals can be analyzed in amicroprocessor controlling the flow meter within the AEC and sheath gasflow can be adjusted accordingly. In both scenarios described above, thenebulizer is operating continuously generating aerosol all the time. Theaerosol generator can also be controlled based on the patient triggeringmechanism. Again, the impulses based on NAVA technology could activategeneration of aerosol before a patient is starting inspiration due tosignal analysis by the microprocessor built in within AEC. The aerosolgenerator activation can be supported with the increased sheath gas flowas described above. The end of inspiration as well as aerosol generationcan be determined based on the strength of the neuronal signal asdescribed by NAVA.

The invention will be illustrated in more detail with reference to thefollowing Examples, but it should be understood that the presentinvention is not deemed to be limited thereto.

EXAMPLES Example 1 Oxygen Dilution by Different Adaptor Designs

This protocol was designed to characterize the aerosol dilution effectof three different ventilation circuit adaptor adaptors for use withCPAP: a) the adaptor as described by U.S. patent publication2006/0120968 to Niven et al. (adaptor 1); b) a ‘high resistant adaptor’(adaptor 2 as shown in FIGS. 1A, 2A-4, 10 mm aerosol flow tube (L1 inFIG. 2B)); and c) a ‘low resistant adaptor’ (adaptor 3 as shown in FIGS.1A, 2A-4, 5-6 mm aerosol flow tube (L1 in FIG. 2B)). In order to measurethe dilution of aerosol, gases with two different concentrations ofoxygen were used: 100% oxygen gas for aerosol flow and 21% oxygen gasfor CPAP flow. The adaptors were tested under different CPAP flowconditions (6, 8, 10 and 12 L/min), and different steady state,potential inspiratory flows (0.3, 1.04, 3.22 and 5.18 L/min). Theaerosol flow was constant at 3 L/min, the CPAP pressure maintained at 5cm H₂O for all tested conditions.

The CPAP ventilation circuit was based on the Infant Star additionalblended gas source with a flow meter. One end of the inspiratory limb ofthe circuit was connected to the blended gas flow meter and the otherend to the inspiratory port of the tested ventilation circuit adaptor.The expiratory limb of the circuit was connected to the expiratory portof adaptor and the other end to a 5 cm H₂O PEEP valve. The ET tube portof the tested adaptor was connected to a rotameter through a ‘T’connector. The oxymeter was connected to the circuit via this ‘T’connector. A pressure manometer was connected to the adaptor via thepressure monitoring port. The oxymeter and pressure manometer werecalibrated prior the initiation of the experiment. The oxygen tube wasconnected to the flow meter of the oxygen source and the other end tothe aerosol port of the adaptor mimicking the aerosol flow. There were 5recordings of every measurement done, 10 seconds apart. Collected datarepresent the oxygen concentration, and are presented as dilution factorvalue calculated using the equation:

Y=x−21%/79%

The results are presented as dilution factor values in Table 1. Both theadaptor 1 and the adaptor 2 (high resistance adaptor) showed norelationship between the different CPAP flows and the differentinspiratory flows, i.e., no dilution was observed at any testedcombination. Whenever inspiratory flow exceeded aerosol flow (i.e., waslarger than approximately 3 L/min), a dilution effect was observed, aswas expected. The adaptor 2 demonstrated somewhat better results for thecondition when inspiratory flow was equal to aerosol flow. The adaptor 3(low resistant CPAP adaptor) did not perform as well as the other twoadaptors. A significant dilution effect was observed with CPAP flowshigher than 4 L/min in the adaptor 3. The greatest dilution effect wasnoted for a CPAP flow of 12 L/min with a 0.8 dilution effect, comparedto almost no dilution with the other two adaptors.

Overall, the design of the adaptors 2 and 3 is much different than thedesign of the adaptor 1. The inner volumes of both adaptors 2 and 3 aresimilar to the inner volume of the standard ‘Y’ connector, which allowsfor much safer use in combination with any type of breathing support.These adaptors can be used interchangeably for aerosol delivery underdifferent ventilatory support conditions or just for ventilation duringinterim periods in aerosol therapy.

In summary, in this study, the adaptor 2 was superior in comparison toother two tested adaptors in introducing and directing undiluted oxygentowards the patient's interface due to the selection of L1.

TABLE 1 Prior Art Adaptor-Adaptor1 High Res. Adaptor-Adapto2 Low Res.Adaptor-Adaptor 3 Insp Flow CPAP Flow L/min CPAP Flow L/min CPAP FlowL/min 0.3 L/min 4 6 8 10 12 4 6 8 10 12 4 6 8 10 12 #1 1 0.98734 0.987340.9747 0.98734 0.9873 1     1 0.98734 0.98734 0.98734 0.94937 0.924050.86076 0.79747 #2 1 1 0.97468 0.9873 0.98734 1 1.01266 1 1 0.987340.98734 0.94937 0.89873 0.86076 0.79747 #3 1 0.98734 0.98734 0.98730.98734 0.9873 1     1 0.98734 0.98734 0.98734 0.94937 0.89873 0.860760.79747 #4 1 1 0.97468 0.9873 0.98734 0.9873 1     0.98734 0.987340.98734 0.98734 0.93671 0.91139 0.86076 0.79747 #5 0.987342 1 0.987340.9873 0.98734 0.9873 1     1 1 0.98734 0.98734 0.94937 0.88608 0.8481 0.78481 mean 0.997468 0.99494 0.98228 0.9848 0.98734 0.9899 1.002530.99747 0.99241 0.98734 0.98734 0.94684 0.9038  0.85823 0.79494 SD0.005661 0.00693 0.00693 0.0057 1.2E−16 0.0057 0.00566 0.00566 0.006931.2E−16 1.2E−16 0.00566 0.01443 0.00566 0.00566 Insp Flow 1.04 L/min #10.987342 0.97468 0.97468 0.9873 0.98734 0.9873 0.98734 0.97468 0.987340.97468 0.98734 0.96203 0.91139 0.8481  0.79747 #2 0.987342 0.974680.98734 0.9873 0.98734 0.9747 0.97468 0.98734 0.98734 0.98734 0.974680.94937 0.89873 0.86076 0.79747 #3 0.974684 0.96203 0.97468 0.98730.98734 0.9873 0.98734 0.98734 0.98734 0.98734 0.98734 0.96203 0.898730.86076 0.77215 #4 0.974684 0.97468 0.97468 0.9873 0.98734 0.97470.98734 0.98734 0.98734 0.98734 0.97468 0.96203 0.91139 0.8481  0.79747#5 0.974684 0.97468 0.97468 0.9873 0.98734 0.9747 0.97468 0.987340.97468 0.98734 0.98734 0.96203 0.91139 0.8481  0.79747 mean 0.9797470.97215 0.97722 0.9873 0.98734 0.9797 0.98228 0.98481 0.98481 0.984810.98228 0.95949 0.90633 0.85316 0.79241 SD 0.006933 0.00566 0.005661E−16 1.2E−16 0.0069 0.00693 0.00566 0.00566 0.00566 0.00693 0.005660.00693 0.00693 0.01132 Insp Flow 3.22 L/min #1 0.936709 0.93671 0.936710.9367 0.92405 0.9873 0.98734 0.98734 0.98734 0.98734 0.94937 0.898730.83544 0.77215 0.68354 #2 0.924051 0.94937 0.93671 0.9241 0.911390.9873 0.98734 0.98734 0.98734 0.97468 0.93671 0.88608 0.8481  0.784810.68354 #3 0.936709 0.94937 0.93671 0.9367 0.91139 1 0.98734 0.987340.98734 0.97468 0.94937 0.88608 0.8481  0.77215 0.68354 #4 0.9240510.94937 0.92405 0.9367 0.92405 1 0.98734 0.98734 0.98734 0.97468 0.949370.88608 0.8481  0.77215 0.68354 #5 0.936709 0.93671 0.93671 0.92410.92405 1 0.98734 1 0.97468 0.98734 0.94937 0.88608 0.8481  0.772150.6962  mean 0.931646 0.9443 0.93418 0.9316 0.91899 0.9949 0.987340.98987 0.98481 0.97975 0.94684 0.88861 0.84557 0.77468 0.68608 SD0.006933 0.00693 0.00566 0.0069 0.00693 0.0069 1.2E−16 0.00566 0.005660.00693 0.00566 0.00566 0.00566 0.00566 0.00566 Insp Flow 5.18 L/min #10.696203 0.67089 0.6962  0.6962 0.68354 0.5949 0.72152 0.78481 0.797470.78481 0.75949 0.70886 0.67089 0.62025 0.59494 #2 0.696203 0.670890.6962  0.6835 0.68354 0.5949 0.72152 0.78481 0.81013 0.78481 0.759490.70886 0.67089 0.63291 0.58228 #3 0.683544 0.6962 0.6962  0.68350.68354 0.6203 0.73418 0.77215 0.79747 0.78481 0.75949 0.6962  0.658230.62025 0.58228 #4 0.696203 0.68354 0.68354 0.6835 0.6962  0.59490.73418 0.77215 0.81013 0.79747 0.74684 0.6962  0.65823 0.62025 0.58228#5 0.683544 0.6962 0.68354 0.6835 0.68354 0.5823 0.73418 0.77215 0.810130.79747 0.74684 0.70886 0.65823 0.62025 0.58228 mean 0.691139 0.683540.69114 0.6861 0.68608 0.5975 0.72911 0.77722 0.80506 0.78987 0.754430.7038  0.66329 0.62278 0.58481 SD 0.006933 0.01266 0.00693 0.00570.00566 0.0139 0.00693 0.00693 0.00693 0.00693 0.00693 0.00693 0.006930.00566 0.00566

Example 2 Resistance Measurements of Different Adaptor Designs

The purpose of this study was to evaluate the operationalcharacteristics of different ventilation circuit adaptors used foraerosol introduction into the CPAP ventilation circuit at the level of a‘Y’ connector. Operational characteristics were assessed based on theresistance values of different adaptors tested under typical ventilationconditions for the potential targeted neonatal population.

The protocol was designed to characterize the operationalcharacteristics of three different ventilation circuit adaptors and astandard ‘Y’ connector under dynamic flow conditions as intermittentmechanical ventilation (IMV): a) the adaptor as described by US patentpublication 2006/0120968 to Niven et al. (the adaptor 1); b) a ‘highresistant CPAP adaptor’ (the adaptor 2 as shown in FIGS. 1A, 2A-4, 10 mmaerosol flow tube); c) a ‘low resistant adaptor’ (the adaptor 3 as shownin FIGS. 1A, 2A-4, 5-6 mm aerosol flow tube); and d) a ‘standard Yconnector’ (the adaptor 4). These CPAP adaptors were tested under twodifferent inspiratory flow conditions (approximately 1 and 3 L/minrespectively). The operational characteristics of different adaptorswere based on resistance measurements performed by airway manometry andpneumotachography.

The ventilator circuit was based on the Harvard small animal ventilator.One end of the inspiratory limb of the circuit was connected to theinspiratory port of the ventilator and the other end to the inspiratoryport of the tested ventilation circuit adaptor. The expiratory limb ofthe circuit was connected to the expiratory port of the adaptor and theother end to the expiratory port of the Harvard ventilator. A pressuremanometer was connected to the adaptor via the pressure monitoring port.The pressure manometer was calibrated prior the initiation of theexperiment. The aerosol port of the adaptor was securely closed. Therewas 1 recording for every measurement done based on the PEDScalculations from at least 10 breathing cycles. Data represent the meanand standard error of the mean (SEM) values of inspiratory, expiratory,and total resistance.

The results are presented as mean and SEM values for total, inspiratoryand expiratory resistance in Table 2. None of the tested adaptors showedhigher resistance values (within 10%) compared to the ‘standard Yconnector’ (the adaptor 4), which served as a reference for this test.In fact, the ‘high resistant adaptor’ (the adaptor 2) had lowerresistance values measured under two different inspiratory flowconditions than the ‘standard Y connector’.

TABLE 2 PIF = 1.3-1.4 mL/min PIF = 2.9-3.2 mL/min Resistance mL/cm H₂OResistance mL/cm H₂O Inspiratory Expiratory Total Inspiratory ExpiratoryTotal Adaptor mean SEM mean SEM mean SEM mean SEM mean SEM Mean SEM #128.02 0.68 35.56 0.12 24.62 0.06 33.58 0.23 57 0.7 39.98 1.46 #2 27.90.44 32.08 0.04 25.34 0.07 26 0.22 49.78 0.28 30.43 0.19 #3 33.63 0.2835.55 0.13 27.11 0.18 31.57 0.18 55.17 0.57 38.74 0.21 #4 32.04 0.2830.26 5.5 26.61 0.7 29.98 0.4 55.39 0.33 36.46 0.27

Example 3 Preclinical Study

A preclinical study on preterm lamb has been aimed on proving theefficacy of aerosolized lucinactant for inhalation for prevention ofRDS, and has utilized an embodiment of the ventilatory circuit adaptorof the invention as shown in FIGS. 1A, 2A. Four preterm lambs withgestation age of 126-128 days were treated with CPAP after pretermdelivery. Within 30 minutes after birth the aerosolized surfactanttreatment was initiated. The adaptor has efficiently delivered aerosolto the animals without any noted adverse events.

While the invention has been described in detail and with reference tospecific examples thereof, it will be apparent to one skilled in the artthat various changes and modifications can be made therein withoutdeparting from the spirit and scope thereof.

REFERENCES

-   1. Kattwinkel, J., et al., Technique for intrapartum administration    of surfactant without requirement for an endotracheal tube. J    Perinatol, 2004. 24: p. 360-365.-   2. Trevisanuto, D., et al., Laryngeal mask airway used as a delivery    conduit for the administration of surfactant to preterm infants with    respiratory distress syndrome. Biol Neonate, 2005. 87(4): p. 217-20.-   3. Richardson, C. and A. Jung, Effect of continuous positive airway    pressure on pulmonary function and blood gases of infants with    respiratory distress syndrome. Pediatr Res, 1978. 12: p. 771-4.-   4. Gaon, P., et al., Assessment of effect of nasal continuous    positive pressure on laryngeal opening using fibre optic    laryngoscopy. Arch Dis Child Fetal Neonatal Ed, 1999. 80(3): p.    F230-2.-   5. Thomson, M., et al., Treatment of immature baboons for 28 days    with early nasal continuous positive airway pressure. Am J Respir    Crit Care Med, 2004. 169(9): p. 1054-62.-   6. Verder, H., et al., Surfactant therapy and nasal continuous    positive airway pressure for newborns with respiratory distress    syndrome. Danish-Swedish Multicenter Study Group. N Engl J    Med, 1994. 331(16): p. 1051-5.-   7. Verder, H., et al., Nasal continuous positive airway pressure and    early surfactant therapy for respiratory distress syndrome in    newborns of less than 30 weeks' gestation. Pediatrics, 1999.    103(2): p. E24.-   8. Dolovich, M., Influence of inspiratory flow rate, particle size,    and airway caliber on aerosolized drug delivery to the lung. Respir    Care, 2000. 45(6): p. 597-608.-   9. Becquemin, M., et al., Particle deposition and resistance in the    nose of adults and children. Eur Respir J, 1991. 4: p. 694-702.-   10. Salmon, B., N. Wilson, and M. Silverman, How much aerosol    reaches the lungs of wheezy infants and toddlers. Arch Dis    Child, 1989. 65: p. 401-403.-   11. Fink, J. B., et al., Can high efficiency aerosol delivery    continue after extubation. Crit Care, 2005. 9(Suppl 1): p. P129.-   12. Beck, J., et al., Prolonged neural expiratory time induced by    mechanical ventilation in infants. Pediatr Res, 2004. 55(5): p.    747-754.

1. An adaptor for delivering an aerosolized active agent to a patientwith concomitant positive pressure ventilation, comprising: a) anaerosol flow channel having an aerosol inlet port and a patientinterface port, and defining an aerosol flow path from the aerosol inletport to and through the patient interface port; and b) a ventilation gasflow channel in fluid communication with the aerosol flow channel andhaving a gas inlet port and a gas outlet port, and defining aventilation gas flow path from the gas inlet port to and through the gasoutlet port, wherein the ventilation gas flow path is at least partiallyoffset from the aerosol flow path and at least partially encircles theaerosol flow path.
 2. The adaptor of claim 1, further comprising a valveat the aerosol inlet port.
 3. The adaptor of claim 2, wherein the valveis sufficiently flexible to allow introduction of at least one of aninstrument, a catheter, a tube, or a fiber into and through at least oneof the aerosol flow channel and the patient interface port, whilemaintaining positive ventilatory pressure.
 4. The adaptor of claim 1,wherein the aerosol flow channel defines a substantially straightaerosol flow path, a curved aerosol flow path, or an angled aerosol flowpath.
 5. The adaptor of claim 1, wherein the aerosol flow channel has asubstantially uniform cross-sectional area.
 6. The adaptor of claim 1,wherein the aerosol flow channel has a greater cross sectional area atthe aerosol inlet port than at the patient interface port.
 7. Theadaptor of claim 1, wherein fluid communication between the aerosol flowchannel and the ventilation gas flow channel occurs via at least oneaperture.
 8. The adaptor of claim 1, wherein the ventilation gas flowchannel forms a chamber that includes the gas inlet port, the gas outletport and the patient interface port, wherein the aerosol flow channel iscontained within the chamber and extends from the aerosol inlet port atone end of the chamber through the chamber to an aerosol outlet portwithin the chamber and is recessed from the patient interface port atthe opposite end of the chamber, wherein the aerosol flow channel is ofa sufficient length to extend beyond the gas inlet and outlet ports. 9.The adaptor of claim 8, wherein the aerosol outlet port is recessed fromthe patient interface port by at least about 8 millimeters.
 10. Theadaptor of claim 8, wherein the chamber has a volume between the aerosoloutlet port and the patient interface port of at least about 1.4milliliters.
 11. The adaptor of claim 8, further comprising a one-wayvalve at the aerosol outlet port.
 12. A method for delivering anaerosolized active agent to a patient with concomitant positive pressureventilation, the method comprising: a) providing a positive pressureventilation circuit comprising a positive pressure generator forproducing a pressurized ventilation gas and a delivery conduit fordelivering an amount of the pressurized ventilation gas to the patientand for directing a flow of exhalation gas from the patient; b)providing an aerosol generator for producing the aerosolized activeagent; c) providing a patient interface for delivering the ventilationgas, the aerosolized active agent or the mixture thereof to the patient;d) connecting the positive pressure ventilation circuit and the aerosolgenerator to the patient interface through an adaptor, the adaptorcomprising: i) an aerosol flow channel having an aerosol inlet port anda patient interface port, and defining an aerosol flow path from theaerosol inlet port to and through the patient interface port; and ii) aventilation gas flow channel in fluid communication with the aerosolflow channel and having a gas inlet port and a gas outlet port, anddefining a ventilation gas flow path from the gas inlet port to andthrough the gas outlet port, wherein the ventilation gas flow path is atleast partially offset from the aerosol flow path and at least partiallyencircles the aerosol flow path; e) providing the pressurizedventilation gas to the patient, wherein the volume of the pressurizedventilation gas is regulated by at least one of the length of theaerosol flow channel and the pressure created by an increased demand forair which is not matched by the aerosol flow; and f) providing anaerosol flow of the aerosolized active agent to a chamber inside theadaptor such that aerosol flow is introduced below the ventilation gasflow channel wherein the aerosol flow is selected to match the patient'sinspiratory flow and thereby providing the aerosolized active agent tothe patient.
 13. A system for delivering a propelled aerosolized activeagent with concomitant positive pressure ventilation to a patient,comprising: a) a positive pressure ventilation circuit comprising apositive pressure generator for producing pressurized ventilation gasand a delivery conduit for delivering the pressurized ventilation gas tothe patient and for directing a flow of exhalation gas from the patient;b) an aerosol generator for producing an aerosolized active agent; c) apatient interface for delivering the ventilation gas and the aerosolizedactive agent to the patient; d) an adaptor in communication with thepositive pressure ventilation circuit, the aerosol generator and thepatient interface; e) an aerosol entrainment chamber adapted to producethe propelled aerosolized active agent, wherein the aerosol entrainmentchamber is in communication with the aerosol generator; and f) anauxiliary circuit in connection with the delivery conduit for deliveringthe pressurized ventilation gas to the patient, wherein the auxiliarycircuit comprises a first auxiliary conduit connecting the deliveryconduit and the aerosol entrainment chamber and a second auxiliaryconduit connecting the aerosol entrainment chamber and the adaptor,wherein the first auxiliary conduit is adapted to accommodate a portionof the pressurized ventilation gas which is removed from a main flow ofthe pressurized ventilation gas directed toward the adaptor, and todeliver the portion of the pressurized ventilation gas to the aerosolentrainment chamber for combining with the aerosolized active agent toform the propelled aerosolized active agent, and the second auxiliaryconduit is adapted to deliver the propelled aerosolized active agent tothe adaptor.
 14. The system of claim 13, wherein the adaptor comprises:i) an aerosol flow channel having an aerosol inlet port and a patientinterface port, and defining an aerosol flow path from the aerosol inletport to and through the patient interface port; and ii) a ventilationgas flow channel in fluid communication with the aerosol flow channeland having a gas inlet port and a gas outlet port, and defining aventilation gas flow path from the gas inlet port to and through the gasoutlet port, wherein the ventilation gas flow path is at least partiallyoffset from the aerosol flow path and at least partially encircles theaerosol flow path.
 15. The system of claim 14, wherein the adaptorfurther comprises a valve at the aerosol inlet port.
 16. The system ofclaim 15, wherein the valve is a slit valve or a cross-slit valve. 17.The system of claim 15, wherein connection of the aerosol generator tothe adaptor causes the valve to open, and disconnection of the aerosolgenerator from the adaptor causes the valve to close.
 18. The system ofclaim 15, wherein the valve, when closed, is sufficiently flexible toallow introduction of at least one of an instrument, a catheter, a tubeor a fiber into and through the aerosol flow channel and the patientinterface port, while maintaining positive ventilatory pressure.
 19. Thesystem of claim 13, wherein the patient interface comprises a mask or atleast one nasal prong.
 20. A method for delivering a propelledaerosolized active agent with concomitant positive pressure ventilationto a patient, the method comprising the steps of: a) providing apositive pressure ventilation circuit comprising a positive pressuregenerator for producing pressurized ventilation gas and a deliveryconduit for delivering the pressurized ventilation gas to the patientand for directing a flow of exhalation gas from the patient; b)providing an aerosol generator for producing an aerosolized activeagent; c) providing a patient interface for delivering the ventilationgas and the aerosolized active agent to the patient; d) providing anadaptor in communication with the positive pressure ventilation circuit,the aerosol generator and the patient interface; e) providing an aerosolentrainment chamber in communication with the aerosol generator; f)providing an auxiliary circuit in connection with the delivery conduitfor delivering the pressurized ventilation gas to the patient, whereinthe auxiliary circuit comprises a first auxiliary conduit connecting thedelivery conduit and the aerosol entrainment chamber and a secondauxiliary conduit connecting the aerosol entrainment chamber and theadaptor; g) removing a portion of the pressurized ventilation gas from amain flow of the pressurized ventilation gas directed toward the adaptorto the first auxiliary conduit and directing the portion of thepressurized ventilation gas to the aerosol entrainment chamber, therebycombining the portion of the pressurized ventilation gas with theaerosolized active agent to form a propelled aerosolized active agent;h) directing the propelled aerosolized active agent to the secondauxiliary conduit, thereby delivering the propelled aerosolized activeagent to the adaptor; and i) providing the propelled aerosolized activeagent and the pressurized ventilation gas to the patient interface,thereby delivering the pressurized ventilation gas and the propelledaerosolized active agent to the patient.
 21. The method of claim 20,wherein the adaptor is as claimed in claim 1.